Potent antiretroviral therapy (ART) has dramatically reduced morbidity and mortality due to HIV/AIDS in the United States, and is beginning to have an impact in resource-limited settings. Unfortunately, toxicity due to long-term ART has become a major problem. Many of the toxicities of HIV therapy are due to mitochondrial toxicity of nucleoside reverse transcriptase inhibitors (NRTI), essential components of most ART regimens. Although it has been suggested that oxidant stress is the fundamental mechanistic link between mitochondrial damage and clinical manifestations of toxicity, there are presently no specific therapies for most ART toxicities. The aims of this Research Career Award are to test the hypothesis that increased oxidant stress resulting from NRTI-induced mitochondrial dysfunction is a critical step in the pathway to NRTI toxicity by: 1) establishing a cohort of HIV-infected patients to confirm that this oxidant stress can be reliably quantified by measuring in vivo production of F2-isoprostanes (F2-IsoPs), unique prostaglandin-like compounds formed by free radical-catalyzed peroxidation of arachidonic acid; 2) performing a randomized, placebo-controlled pilot study using vitamins C, E, and alpha-lipoic acid to identify which antioxidant most effectively reduces plasma F2-IsoP levels in HIV-infected patients; and 3) using data from the pilot study to design a large clinical trial of the efficacy of antioxidant therapy in preventing and/or reversing oxidant stress-associated NRTI toxicities in HIV-infected patients. This award will provide for the career development of an investigator with a patient-oriented research focus in the area of oxidant stress, antiretroviral toxicity, and the use of antioxidants as complementary therapies in HIV. The candidate will be guided by two co-mentors, one with expertise in HIV/AIDS clinical investigation (Dr. David Haas) and the other an accomplished investigator in the field of oxidant stress and co-discoverer of the F2-IsoPs (Dr. Jason Morrow). These co-mentors, together with a rich research environment at the candidate's institution, will ensure that the candidate makes important discoveries in the area of oxidant stress and antioxidants during HIV therapy while strengthening his existing knowledge base and research skills and acquiring new skills. The candidate's long-term goal is to develop into an independent clinical investigator in this field of study.